Escape from adaptive T-cell immunity through mutation of viral antigenic structure is a cardinal feature in the pathogenesis of SIV/HIV infection and a major obstacle to antiretroviral vaccine development. However, the molecular determinants of this phenomenon at the T-cell receptor (TCR)?antigen interface are unknown. This study examines how the T cell response interacts with the changing antigenic structure of viral antigens at the level of individual T cell clones.